title: Plasmodium falciparum Polymorphisms associated with ex vivo drug susceptibility and clinical effectiveness of artemisinin-based combination therapies in Benin.
abstract: Artemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association of Plasmodium falciparum polymorphisms and ex vivo drug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n = 96), fixed-dose artesunate-amodiaquine (n = 96), and sulfadoxine-pyrimethamine (n = 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed. pfcrt, pfmdr1, pfmrp1, pfdhfr, and pfdhps polymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates by Plasmodium lactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for the pfmdr1 N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance of pfmdr1 N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection of pfmdr1 loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical, ex vivo, molecular, and pharmacological data is warranted.
authors.affiliation: Institut de Médecine et d'Epidémiologie Appliquée, Bichat-C. Bernard Hospital, Paris, France.
authors.forename: Sabina
authors.initials: S
authors.lastname: Dahlström
authors.forename: Agnès
authors.initials: A
authors.lastname: Aubouy
authors.forename: Oumou
authors.initials: O
authors.lastname: Maïga-Ascofaré
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Faucher
authors.forename: Abel
authors.initials: A
authors.lastname: Wakpo
authors.forename: Sèm
authors.initials: S
authors.lastname: Ezinmègnon
authors.forename: Achille
authors.initials: A
authors.lastname: Massougbodji
authors.forename: Pascal
authors.initials: P
authors.lastname: Houzé
authors.forename: Eric
authors.initials: E
authors.lastname: Kendjo
authors.forename: Philippe
authors.initials: P
authors.lastname: Deloron
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Bras
authors.forename: Sandrine
authors.initials: S
authors.lastname: Houzé
mesh_terms: D000655:Amodiaquine / Q000031:analogs & derivatives / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D004338:Drug Combinations; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D000078102:Lumefantrine; D008297:Male; D015767:Mefloquine / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D013413:Sulfadoxine / Q000494:pharmacology
chemical_list: D000655:Amodiaquine; D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine; D015767:Mefloquine; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011739:Pyrimethamine; D011803:Quinine; D013413:Sulfadoxine; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C515299:amodiaquine, artesunate drug combination; C001205:fanasil, pyrimethamine drug combination; C039060:artenimol; C047386:desethylamodiaquine; C031327:artemisinin